Childhood tuberculosis

Updated diagnosis and treatment of childhood tuberculosis

Shou-Chien Chen, Kwo-Liang Chen, Kou-Huang Chen, Shun-Tien Chien, Kow-Tong Chen
Taiwan, China

Data sources: The literature from a range of sources

was reviewed and synthesized to provide an overview
of the contemporary approaches for the diagnosis and
treatment of childhood TB.
Results: This review summarizes the clinical,
radiological, bacteriological, and immunological
approaches to diagnose TB infection and disease in
children. In addition, we summarize the updated
guidelines for the treatment of TB in children.
Conclusions: The development of better diagnostic
and therapeutic methods for childhood TB remains a
significant challenge. As the strategies for diagnosis and
treatment of childhood TB continue to improve and the
knowledge base increases, the implementation of these
strategies will be crucial.
World J Pediatr 2013;9(1):9-16
Key words: childhood;
diagnosis;
treatment;
tuberculosis

Author Affiliations: Department of Family Medicine, Da-Chien

General Hospital, Taiwan, China (Chen SC); General Education
Center, Ta Tung University, Taiwan, China (Chen SC); Department of
Industrial Engineering and Management, China University of Science
and Technology, Taiwan, China (Chen KL, Chen KH); Chest Hospital,
Department of Health, Executive Yuan, Taiwan, China (Chien ST);
Department of Public Health, College of Medicine, National Cheng Kung
University, China (Chen KT)
Corresponding Author: Kow-Tong Chen, Department of Public Health,
College of Medicine, National Cheng-Kung University, No. 1, University
Road, Taiwan, China (Tel: 886-6-2353535 ext 5563; Fax: 886-6-2359033;
Email: ktchen@mail.ncku.edu.tw)
doi: 10.1007/s12519-013-0404-6
Children's Hospital, Zhejiang University School of Medicine, China and
Springer-Verlag Berlin Heidelberg 2013. All rights reserved.

Introduction

hildhood tuberculosis (TB) accounts for

approximately 15%-40% of all TB cases. [1-5]
High rates of transmission are sustained in TBendemic areas due to high case density and prolonged
diagnostic delay. [6] Because childhood TB reflects
ongoing transmission, children are most often affected
in areas where the adult epidemic is poorly controlled.[7]
In addition, childhood TB remains neglected for various
reasons, including the difficulty in diagnosing pulmonary
TB, the lack of scientific studies on childhood TB, the
largely unknown outcomes of children with TB, and the
belief that childhood TB is not an important factor in
TB control.[8,9] In recent years, there have been several
important developments in the diagnosis and treatment
of childhood TB infection and disease. This article
provides a brief overview of current controversies and
recent advances in the care of children with TB with an
emphasis on intrathoracic disease.

Data collection

We initially collected all of the articles that were

published from January 2002 to June 2012, which
described children who were affected by TB. These
articles were obtained by searching MEDLINE using
the key words "childhood tuberculosis" and "diagnosis
of tuberculosis or management of tuberculosis". Articles
that were not published in the English language, those
without an abstract (which were assumed not to be
original), and opinion articles were excluded from
the review. After selecting the articles, the relevant
information was extracted and classified according to
TB diagnosis, TB management, the country of the first
author, the year of the publication, and the study design.
Literature searching was performed in May 2012
and June 2012. Using the search terms previously
described, 163 articles were retrieved from MEDLINE.
Finally, 109 of them were considered to be relevant.
The first authors of these articles were primarily from
India, South Africa, the United Kingdom, the United
States, Germany, and Australia. About 35% of the
articles, which belonged to original category were from
India. After analyzing the abstracts of the articles, we
found that 85% of the studies were retrospective, 10%

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Review article

Background: Childhood tuberculosis (TB) accounts

for a significant proportion of the global tuberculosis
disease burden. However, current and previous efforts
to develop better diagnostic, therapeutic, and preventive
interventions have focused on TB in adults, and
childhood TB has been relatively neglected. The purpose
of this review is to provide an update on the diagnostic
and therapeutic recommendations for childhood TB
with an emphasis on intrathoracic disease.

World Journal of Pediatrics

were prospective, and 5% were other designs.

Diagnosis of TB infection

Review article

Tuberculin skin test

A positive tuberculin skin test (TST) reaction has been
used as a hallmark of infection with M. tuberculosis,
which occurs within 3 to 6 weeks of infection but
occasionally up to 3 months after infection and remains
positive for life time even after treatment.[10-12] The test
is read 48-72 hours after injection. The Mantoux test is
the standard tuberculin test that is recommended for use,
which involves an intradermal injection of 2 tuberculin
unit purified protein derivative (TU PPD). [13] The
evoked reaction is dependent on the amount of antigen
administered; however, there is no linear relationship
between the reaction and an increasing strength of
the antigen dose.[14] A prior Bacillus Calmette-Gurin
(BCG) vaccine at birth may influence the PPD reaction
under 3 years of age, but does not interfere with PPD
reaction above 3 years of age.[15,16] When the patient
returns for a TST reading after 72 hours but before the
7th day post-injection, a positive test is still valid.[17]
A repeat test may be needed if there is no induration
and the wheals appear after the stipulated time for
reading. A repeat tuberculin test, when required, should
preferably be performed on the opposite arm.[17] In the
United Kingdom,[18] a TST is considered positive when
the induration is 5 mm or more in diameter in patients
without prior BCG vaccination. In contrast, the World
Health Organization (WHO) guidelines suggest that a
TST is positive when the induration is more than 10 mm
in diameter in patients without prior BCG vaccination
and more than 15 mm in diameter in patients with prior
BCG vaccination.[19] The guidelines in Taiwan use a
risk categorization that is based on epidemiological and
clinical factors (Table 1).[20]

Tuberculin skin tests are prone to both falsenegative and false-positive results. In otherwise
immunocompetent children with culture-documented
TB, 10%-15% of these children do not initially exhibit
TST reactivity. [21] Host factors, such as young age,
poor nutrition, immunosuppression, viral infections,
recent TB infection, and disseminated TB disease, can
further decrease TST reactivity.[22,23] Most of consensus
documents concerning TST interpretation agree that
malnutrition can cause a TST false negative result;[22]
however, some studies[23,24] conclude that only some comorbidities can modify TST, without specific nutritional
status. In addition, false-positive TST results may occur
after BCG vaccination and exposure to environmental
non-tuberculous mycobacteria.[25] In many children and
adults who receive BCG vaccination, skin reaction can
be boosted by antigenic stimulation during serial testing
with TST.[26]

Interferon-gamma release assays

Because of the limitations of TST, new diagnostic tests
have been developed. Interferon-gamma release assays
(IGRAs) are blood-based assays and have recently
become available. These T-cell-based assays rely on the
stimulation of host blood cells with M. tuberculosisspecific antigens (early secretory antigenic target-6,
the culture filtrate protein 10, and QuantiFERON-TB
Gold TB 7.7), and are used to measure the production
of interferon-. Two available commercial assays, the
T-Spot TB assay (Oxford Immunotec, Inc., Abingdon,
UK) and the QuantiFERON-TB Gold assay (Cellestis,
Ltd., Carnegie, Victoria, Australia) are compared,
with TST for the detection of both active disease and
latent tuberculosis infection. [27] Overall, the results
indicate that IGRAs have a modest predictive value,
which is similar to that of TST. In the settings with a
low TB incidence, the IGRAs demonstrated a higher

Table 1. Interpretation of positive Mantoux tests in children

British Thoracic Society[18]
10TU PPD per 0.1 mL

World Health Organization[19]

5TU PPD-S per 0.1 mL
(alternatively 2 TU PPD RT23)
5-14 mm if not BCG vaccinated 5 mm if one of the following:
HIV positive children
Severely malnourished children
(clinical evidence)
>15 mm if BCG vaccinated
10 mm for all other children
whether BCG vaccinated or not

Taiwan Centers for Disease Control[20]

2TU PPD RT23

5 mm if one of the following:

Cancer
Organ transplant
Immunosuppression
10 mm and if one of the following:
Children aged >6 years and BCG vaccinated >6 years or without
BCG vaccinated or with one of following risk factors: close contact
with active TB patients; having family history of TB; having chronic
diseases, such as diabetes
Malnutrition
Drug abuser
>15 mm and if children aged 6 years or BCG vaccinated 6 years
TU: tuberculin unit; PPD: purified protein derivate; BCG: Bacille Calmette-Gurin; HIV: human immunodeficiency virus; TB: tuberculosis.

10

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Childhood tuberculosis

Diagnosis of disease

Clinical features
The diversity of the clinical presentation and the nonspecific nature of the symptoms of TB complicates

the diagnosis. Low-grade or intermittent fever may be

observed but not frequently.[9] A cough of recent onset
that lasts longer than 2 weeks should be suspicious
of TB. [41] Therapeutic trials with anti-TB drugs are
not recommended; however, efforts should be made
to confirm the diagnosis. The clinical signs are often
subtle, and no diagnostic scoring has been adequately
validated.[42]

Chest radiograph
A chest radiograph localizes the site of pathology;
however, this test does not confirm disease etiology.[43]
The chest radiograph of a child with bronchiectasis or
an interstitial lung disease may present non-resolving
shadows with persistent symptoms. Ultrasonography
of the chest is helpful to assess pleural fluid collection,
but decubitus chest X-ray film may reveal similar
information. Computed tomography (CT) has been
useful in identifying the signs of early pulmonary
disease, such as cavitation and intrathoracic hilar
lymphadenopathy.[44] There is no evidence that these
adenopathies indicate active disease or that these
children require different treatments. Consequently,
until demonstrated otherwise, pulmonary CT scanning
and changes in chemoprophylaxis are not justified in
children with tuberculosis infection.[45] Additionally,
central nervous system disease, such as TB meningitis or
a tuberculoma, may be identified by CT. High-resolution
CT offers excellent anatomical visualization.[46] However,
because of the high cost of CT and the high level of
radiation to which the patient is exposed,[43] compared
with other forms of imaging, CT should be reserved for
complicated cases. Both CT and magnetic resonance
imaging (MRI) are particularly helpful in visualizing
the intracranial effect of the disease; however, MRI is
more sensitive in the detection of brain stem lesions
and early perfusion defects in patients with tuberculous
meningitis, and MRI allows for a superior evaluation of
the spine and soft tissue.[47]
Bacteriological diagnosis/confirmation
A confirmation of acid-fast bacilli (AFB) from any
type of body fluid or tissue is the gold standard for the
diagnosis of tuberculosis. Such proof is often lacking in
childhood tuberculosis cases because of the difficulty in
the collection of sputum and because of paucibacillary
primary disease in children. However, positive AFB
test yield in advanced cases may be as high as in adults.
The reported bacteriological positivity is as high as
33% even in early primary disease states, such as hilar
adenopathy.[43,44] Therefore, efforts must be made to
confirm a diagnosis with bacteriological testing in
every case of suspected tuberculosis. The examination of

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11

Review article

specificity (100% and 98% for the QuantiFERONTB assay and the T-Spot assay, respectively) than TST
(58%) in children with TB.[28] A study of children with
TB disease indicated lower sensitivities of the T-spot
TB assay (58%) and the QuantiFERON TB assay
(80%) compared with the TST (83%). [29] A study [30]
indicated a higher sensitivity of 100% and a specificity
of 93% for TST at a cut-off point of >5 mm in
children without BCG vaccination. In BCG-vaccinated
children, the TST cut-off point of >10 mm had a
poor specificity (86%), and the cut-off point of >15
mm results in a reduced sensitivity of 60%. Another
significant problem with IGRAs has been the risk of
indeterminate tests, particularly in younger children
and immunocompromized individuals.[31] The rates of
indeterminate tests are higher for the QuantiFERON-TB
Gold assay than for the Enzyme-linked Immunosorbent
Assay in immunosuppressed individuals.[32,33]
T-cell assays are more specific than TST, but
these tests currently cannot distinguish between active
disease and latent tuberculosis infection.[27] Therefore,
the interpretation of the test results is dependent on
the clinical context. Few studies[34,35] have presented
pediatric T-cell assay data, but none of these studies
assessed age-related performance. Therefore, the
performance of T-cell assays in very young children and
in immunocompromised individuals, such as patients
with human immunodeficiency virus (HIV), is not welldefined. The costs and technical demands of IGRAs
will most likely limit the wide use of these assays in
resource-poor settings where better tests are in high
demand.
Another immune-based approach is the
measurement of the immune response to the
transdermal application of M. tuberculosis MPB-64
antigen. In pilot studies, the MPB-64 skin patch test can
successfully distinguish between active TB and latent
tuberculosis infection (LTBI) (a sensitivity of 88%-98%
and a specificity of 100%).[36]
The search for novel biomarkers in the blood or
urine that can reliably distinguish between active and
latent tuberculosis in children with or without coinfections remains an important goal.[37-39] Well-defined
cohorts of pediatric patients in tuberculosis-endemic
and non-endemic settings will be essential for the
initial screening and future validation of such potential
markers.[40]

World Journal of Pediatrics

Review article

sputum-induced or spontaneous gastric aspirates (GAs),

bronchial washings, and any other appropriate body
fluid may be undertaken. In addition, bronchoalveolar
lavage (BAL) can be performed when available. To
date, the sensitivity and specificity of GA examination
and BAL are similar; however, GA examination is
easier to perform.[48] A gastric aspirate collected in the
early morning is the preferred specimen for most young
children with suspected TB. The aspirate is preferable for
detecting AFB and isolating M. tuberculosis.[49] Clinicians
should collect at least three samples, regardless of the
method that is selected.
Ziehl-Neelsen and fluorochrome stains, such as
auramine and rhodamine stains, have been the standard
and rapid diagnostic tools for TB.[50,51] A Ziehl-Neelsen
stain can reveal AFB only if the sample contains more
than 10 000 bacilli per mL. Recent advances in lightemitting diode (LED) technology have widened the
application of fluorescent microscopy.[52]
Mycobacterial culture of respiratory samples is a
useful method for diagnosis in children with suspected
pulmonary TB. Different culture methods, such as
Lwenstein-Jensen (LJ) medium (solid medium),
radiometric methods (BATEC 12B liquid medium), and
non-radiometric methods (BATEC MGIT 960 system)
(Becton Dickinson Diagnostic Instrument System,
Towson, MD, USA), can be used to confirm a diagnosis
in the paucibacillary state. [53] Newer methods offer
faster results and may be used when available.
New culture-based methods, such as TK medium
(SALUBRIS, Woburn, MA, USA), use multiple
dye indicators, which allow for the early detection
of mycobacterial growth using the naked eye. [54]
Colorimetric systems reduce turnaround times, but
the accuracy and robustness of these methods in
field conditions have not been reported. The drug
susceptibility assay uses an inverted light microscope
to rapidly detect mycobacterial growth in liquid growth
media. [52] This assay has demonstrated excellent
performance in field conditions.
Bacteriophage-based assays use bacteriophage
viruses to infect and detect the presence of viable M.
tuberculosis isolates in clinical samples and culture
isolates. The following two main approaches have been
developed: (1) the use of phage amplification to detect
the presence of mycobacteria and (2) the detection of
the light that is produced by luciferase reporter phages
after infection of live M. tuberculosis. When the assays
detect M. tuberculosis in drug-free samples but fail
to detect M. tuberculosis in drug-containing samples,
the strains are classified as drug susceptible. Phage
assays have a turnaround time of 2-3 days, and these
assays require a similar laboratory infrastructure to that
required for standard cultures. There is no information
12

on the utility of these tests in the diagnosis of childhood

TB.[29]
The use of a gas sensor array electronic nose (E-nose)
to detect different Mycobacterium species in the
headspaces of cultures and sputum samples is another
innovative approach that is currently in development.
The array uses 14 sensors to profile an odor by assessing
the change in the electrical properties of each sensor
when the array is exposed to a specific odor mixture. In
a recent study that analyzed sputum samples from adult
TB and non-TB patients, the E-nose had a sensitivity
of 68% and a specificity of 69%.[55] Additional research
is required to improve the sensitivity and specificity of
this test and determine the potential usefulness of this
test in the diagnosis of childhood TB.

Molecular diagnostics
Diagnostic methods for M. tuberculosis have recently
improved, and nucleic acid-based amplification
techniques (NAATs) now allow for rapid and sensitive
detection in clinical settings. [56,57] Currently, several
assays are commercially available for the detection of M.
tuberculosis bacteria. NAATs that use polymerase chain
reaction (PCR) cannot differentiate between living and
dead bacilli; therefore, these tests continue to produce
positive results even after successful treatment. PCR
tests are positive in 95%-100% of culture-positive cases
but in only 50%-60% of culture-negative cases.[58]
Real-time PCR has become increasingly available
for clinical use, and this test has the advantage of
lower cross-contamination and the ability to identify
rifampicin resistance. The rpoB gene of M. tuberculosis
accounts for more than 95% of rifampicin resistance.
Because rifampicin resistance is usually accompanied
by isoniazid resistance, this test is used as a marker for
multi-drug resistant TB.[29]
Line probe assays (LPAs) are NAATs t h a t
simultaneously detect infection with M. tuberculosis
and amplify regions of drug resistance. These assays
use strip technology in which amplified DNA is applied
to strips that contain probes specific for M. tuberculosis,
isoniazid, and rifampicin resistance. The WHO has
endorsed LPAs for culture and smear-positive clinical
specimens as part of a larger commitment to target and
implement new technology in countries with a high
burden of TB.[59]
In addition, NAATs have been used for the rapid
detection of rifampicin resistance directly from sputum
specimens. The Xpert mycobacterium tuberculosis/
resistance to rifampicin is a cartridge-based, automated
diagnostic test that is rapid and simple to use. This test
correctly identified 98% of bacteria that were resistant
to rifampicin in a large study in adults.[29]

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Childhood tuberculosis
Table 2. World Health Organization recommendations for tuberculosis
treatment regimens for children[60,62]
Setting

Extensive pulmonary
Mild-to-moderate
pulmonary
Mild-to-moderate
pulmonary
Lymphadenitis

Any
High HIV or high
isoniazid resistance
Low HIV or low
isoniazid resistance
High HIV or high
isoniazid resistance
Low HIV or low
isoniazid resistance
Any
Any

Lymphadenitis
Meningitis
Osteoarticular

Anti-TB drug regimens

Intensive Continuation
phase
phase
2HRZE
4HR
2HRZE
4HR
2HRZ

4HR

2HRZE

4HR

2HRZ

4HR

2HRZE
2HRZE

4HR
4HR

H: isoniazid; R: rifampicin; Z: pyrazinamide; E: ethambutol; TB:

tuberculosis; HIV: human immunodeficiency virus; 2HRZ 4HR:
a two-month intensive phase of daily isoniazid, rifampicin, and
pyrazinamide, followed by a four-month continuation phase of daily
isoniazid and rifampicin.
Table 3. Treatment regimens for children recommended by Centers for
Disease Control, Taiwan, China[20]
Category of disease
PTB, mild EPTB
Severe EPTB
TB meningitis
MDR
HIV infection

Anti-TB drug regimens

Intensive phase
2HRZ*
2HRZ*
2HRZA or 2HRZP
Individualized regimens
2HRZ

Continuation phase
4HR
7-10HR
7-10HR
7-10HR

TB: tuberculosis; PTB: pulmonary tuberculosis; EPTB: extrapulmonary tuberculosis; H: isoniazid; R: rifampicin; Z: pyrazinamide;
A: aminoglycoside; P: prothionamide; 2HRZ 4HR: a two month
intensive phase of daily isoniazid, rifampicin, and pyrazinamide
followed by four-month continuation phase of daily isoniazid and
rifampicin; HIV: human immunodeficiency virus. *: Three drugs
(isoniazid, rifampicin, and pyrazinamide) initial regimen are only
recommended in countries where primary resistance to isoniazid under
4%.

Management of tuberculosis

The principles of TB treatment for adults and children

are the same. Combination regimens that are used to
treat active disease aim to eliminate actively replicating,
dormant, and near-dormant mycobacteria. The regimens
consist of a combination of drugs with minimum
toxicity that has different actions, which prevent the
emergence of drug-resistant organisms.[60]
TB treatment consists of two phases: an intensive
phase with a combination of bactericidal drugs to kill
the rapidly growing bacilli and a continuation phase
with fewer drugs to eradicate the slower-growing
persistent bacilli.[60] The adjunctive use of steroids in
TB meningitis treatment has reduced mortality rate and
severe disability.[61]
Fixed-dose combination tablets have increased
adherence to treatment regimens; however, the marked

Drug

Daily dosage (dose range) in mg/kg

Recommended Recommended by
by WHO
Taiwan CDC, China

First-line oral agents

Isoniazid
10-15
Rifampicin
10-20
Pyrazinamide
30-40
Ethambutol
15-25
Injectable agents
Streptomycin
15-20
Amikacin
15-22.5
Kanamycin
15-30
Capreomycin
15-30
Second-line oral bacteriostatics
Prothionamide
15-20
Ethionamide
15-20
Cycloserine
15-20
Para-aminosalicylic acid
150
Fluoroquinolons
Moxifloxacin
7.5-10
Ciprofloxacin
20 twice daily
Levoflaxacin
7.5-10
Ofloxacin
15-20
WHO: World Health Organization.

10-15
10-15
15-20
15-20
20-40
15-30
15-30
15-20
10-15
10-20
150-600

Review article

Disease

Table 4. First line-anti-TB drugs for children currently recommended

by WHO[60,62] and Centers for Disease Control (CDC), Taiwan, China[20]

7.5-10
7.5-10

differences in the absorption, distribution, and excretion

of pharmacological agents in children of various ages
may require dose adjustments. [62] Tables 2 and 3 list
the regimens by disease category that are currently
recommended by the WHO and the Taiwan Centers for
Disease Control (CDC).[20,60,62] Pharmacokinetic studies
have been performed in children and have indicated
that age is a determinant of the serum levels of all firstline anti-TB drugs and that infants and young children
have lower peak serum levels than older children or
adults.[20,60,63,64] The revised recommended dosages are
listed in Table 4.

Drug-resistant tuberculosis
Poor patient compliance to anti-TB therapy is the major
contributory factor to TB control program failure and
has led to increasing drug resistance.[62] Diagnosing
cases who present with symptoms, coupled with
effective treatment to ensure that most are cured,
has contributed to both developing and developed
countries. [65] After the institution of nationwide
Directly Observed Treatment Strategy programmes,
the annual risk of infection declined in Chile, Cuba
and Uruguay. [66] The rates of drug resistance to
any TB drug range from 20% to 80% in different
geographic regions.[62] Resistance should be suspected
when an index case has known resistant TB, when
the child demonstrates initial improvement on antiTB treatment and then deteriorates, or when there is
no response to the initial treatment. Sometimes, the

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13

World Journal of Pediatrics

Review article

deterioration of the child condition after initial antiTB treatment could also be due to the paradoxical
effect of TB therapy, not always due to drug resistance.
Acquired resistance is well-described in adults who are
co-infected with HIV and who were previously treated
for TB, which possibly results from malabsorption of
the anti-TB medications.[67,68] In addition, the presence
of acquired resistance in the pediatric population has
been reported, and children with HIV/TB co-infections
should be closely monitored.[68]
The global epidemiology of drug resistance has
worsen over the past 40 years, particularly with the
emergence and increased recognition of multi-drug
resistant (MDR) and extensively drug resistant (XDR)
tuberculosis.[69] The disease burden of drug resistant
tuberculosis can be reduced by treating contacts at
high risk of TB infection and of progressing from
TB infection to disease. [70] Treatment for MDR TB
disease is expensive and is associated with poor
prognosis and high risk of toxic effects.[71] Principles
for management of drug-resistant TB in children have
been summarized elsewhere.[70] Excellent outcomes
have been reported.[72,73] Current guidelines recommend
using at least four drugs in treatment-nave patients,
including an injectable agent and a fluoroquinolone,
during an initial phase for at least 6 months.[74,75] The
initial phase should be followed by the use of at least
three of the most active and best tolerated drugs during
a 12- to 18-month continuation phase. Standardized
regimens have been developed for settings where drug
susceptibility testing is not available.[76] Six classes of
second-line drugs are available;[76] however, research
regarding the use of these drugs in children is limited,
and multicenter pediatric trials are needed. [74] The
rates of MDR strains (resistant to both isoniazid and
rifampicin), including XDR strains (also resistant
to fluoroquinolones and at least one second-line
injectable agent, such as amikacin, kanamycin, and/or
capreomycin), are increasing around the world.[67]

Latent TB infection
The duration of LTBI treatment varies by region.
In the United States, 9 months of isoniazid is the
recommended regimen for treating drug-susceptible
LTBI in children according to the guidelines of the
American Thoracic Society and the CDC.[77] In contrast,
both the WHO and the National Institute for Health
and clinical Excellence endorse a 6-month isoniazid
regimen for children. [78] In the US Guidelines, the
6-month regimen is an acceptable alternative only
for non-HIV-infected adults. Six months of therapy
provides a substantial degree of protection; but data
suggest that longer regimens are superior.[79] One study
showed that a 3-month regimen of preventive therapy
14

with isoniazid and rifampin was similar to efficacy to

a 9-month regimen of isoniazid alone for treatment of
LTBI in children.[80]

Conclusion

Advances in TB diagnostic tool development over

the last decade have produced promising methods to
overcome the main barriers in TB care and control.
In the future, new tools in the pipeline need to be
rapidly assessed and deployed if these tools are
found to be effective. The use of diagnostic tools
without appropriate treatment constitutes an untenable
situation. Therefore, as we capitalize on technological
advancements, the commitment to treatment should
increase. Closing the gaps between our knowledge
of diagnostics, drugs, and the delivery of patient care
is needed while we wait for the next wave of new
technologies.
Funding: None.
Ethical approval: Not needed.
Competing interest: None.
Contributors: Chen SC and Chen KL contributed equally to
this paper. All authors contributed to the manuscript conception,
design, drafting, revision and appraisal.

References

1 WHO Report. Global tuberculosis control. Epidemiology,

strategy, financing. Geneva: World Health Organization, 2009.
2 Newton SM, Brent AJ, Anderson S, Whittaker E, Kampmann B.
Paediatric tuberculosis. Lancet Infect Dis 2008;8:498-510.
3 Nelson LJ, Wells CD. Global epidemiology of childhood
tuberculosis. Int J Tuberc Lung Dis 2004;8:636-647.
4 Lu TH, Huang RM, Chang TD, Tsao SM, Wu TC. Tuberculosis
mortality trends in Taiwan: a resurgence of non-respiratory
tuberculosis. Int J Tuberc Lung Dis 2005;9:105-110.
5 Yeh YP, Chang HJ, Yang J, Chang SH, Suo J, Chen TH.
Incidence of tuberculosis in mountain areas and surrounding
townships: dose-response relationship by geographic analysis.
Ann Epidemiol 2005;15:526-532.
6 Marais BJ, Obihara CC, Warren RM, Schaaf HS, Gie RP, Donald
PR. The burden of childhood tuberculosis: a public health
perspective. Int J Tuberc Lung Dis 2005;9:1305-1313.
7 Marais BJ. Childhood tuberculosis: epidemiology and natural
history of disease. Indian J Pediatr 2011;78:321-327.
8 Yu MC, Suo J, Huang C, Bai KJ, Lin TP, Luh KT. Annual risk
of tuberculous infection in Taiwan, 1996-1998. J Formos Med
Assoc 1999;98:496-499.
9 Marais BJ, Gie RP, Hesseling AC, Schaaf HS, Lombard
C, Enarson DA, et al. A refined symptom-based approach
to diagnose pulmonary tuberculosis in children. Pediatrics
2006;118:e1350-1359.
10 Hsu KH. Tuberculin reaction in children treated with isoniazid.
Am J Dis Child 1983;137:1090-1092.
11 Chan PC, Chang LY, Wu YC, Lu CY, Kuo HS, Lee CY, et al.

World J Pediatr, Vol 9 No 1 . February 15, 2013 . www.wjpch.com

Childhood tuberculosis
susceptibility testing of Mycobacterium tuberculosis in stool
specimens from patients with pulmonary tuberculosis. J Clin
Microbiol 2010;48:1820-1826.
30 Mndez-Echevarria A, Gonzlez-Muoz M, Mellado MJ,
Baquero-Artigao F, Vecino R, Prez E, et al. Optimizing
interpretation of the tuberculin test using an interferon-gamma
release assay as a reference standard. Pediatr Infect Dis J
2011;30:426-428.
31 Haustein T, Ridout DA, Hartley JC, Thaker U, Shingadia D,
Klein NJ, et al. The likelihood of an indeterminate test result
from a whole-blood interferon-gamma release assay for the
diagnosis of Mycobacterium tuberculosis infection in children
correlates with age and immune status. Pediatr Infect Dis J
2009;28:669-673.
32 Diel R, Loddenkemper R, Nienhaus A. Evidence-based
comparison of commercial interferon-gamma release assays for
detecting active TB: a metaanalysis. Chest 2010;137:952-968.
33 Bergamini BM, Losi M, Vaienti F, D'Amico R, Meccugni B,
Meacci M, et al. Performance of commercial blood tests for
the diagnosis of latent tuberculosis infection in children and
adolescents. Pediatrics 2009;123:e419-424.
34 Rangaka MX, Wilkinson KA, Seldon R, Van Cutsem G, Meintjes
GA, Morroni C, et al. Effect of HIV-1 infection on T-Cell-based
and skin test detection of tuberculosis infection. Am J Respir Crit
Care Med 2007;175:514-520.
35 Gennaro ML. Immunologic diagnosis of tuberculosis. Clin Infect
Dis 2000;30:S243-S246.
36 Nakamura RM, Einck L, Velmonte MA, Kawajiri K, Ang CF,
Delasllagas CE, et al. Detection of active tuberculosis by an
MPB-64 transdermal patch: a field study. Scand J Infect Dis
2001;33:405-407.
37 Boehme C, Molokova E, Minja F, Geis S, Loscher T, Maboko
L, et al. Detection of mycobacterial lipoarabinomannan with
an antigen-capture ELISA in unprocessed urine of Tanzanian
patients with suspected tuberculosis. Trans R Soc Trop Med Hyg
2005;99:893-900.
38 Steingart KR, Henry M, Laal S, Hopewell PC, Ramsay A,
Menzies D, et al. A systematic review of commercial serological
antibody detection tests for the diagnosis of extrapulmonary
tuberculosis. Thorax 2007;62:911-918.
39 Mutetwa R, Boehme C, Dimairo M, Bandason T, Munyati SS,
Mangwanya D, et al. Diagnostic accuracy of commercial urinary
lipoarabinomannan detection in African tuberculosis suspects
and patients. Int J Tuberc Lung Dis 2009;13:1253-1259.
40 Starke JR. Diagnosis of tuberculosis in children. Pediatr Infect
Dis J 2000;19:1095-1096.
41 Marais BJ, Gie RP, Hesseling AC, Schaaf HS, Lombard
C, Enarson DA, et al. A refined symptom-based approach
to diagnose pulmonary tuberculosis in children. Pediatrics
2006;118:e1350-1359.
42 Hesseling AC, Schaaf HS, Gie RP, Starke JR, Beyers N. A
critical review of diagnostic approaches used in the diagnosis
of childhood tuberculosis. Int J Tuberc Lung Dis 2002;6:10381045.
43 Wong KS, Huang YC, Lai SH, Chiu CY, Huang YH, Lin TY.
Validity of symptoms and radiographic features in predicting
positive AFB smears in adolescents with tuberculosis. Int J
Tuberc Lung Dis 2010;14:155-159.
44 Andronikou S, Joseph E, Lucas S, Brachmeyer S, Du Toit
G, Zar H, et al. CT scanning for the detection of tuberculous
mediastinal and hilar lymphadenopathy in children. Pediatr
Radiol 2004;34:232-236.
45 Gmez-Pastrana D, Carceller-Blanchard A. Should pulmonary
computed tomography be performed in children with

World J Pediatr, Vol 9 No 1 . February 15, 2013 . www.wjpch.com

15

Review article

Age-specific cut-offs for the tuberculin skin test to detect latent

tuberculosis in BCG-vaccinated children. Int J Tuberc Lung Dis
2008;12:1401-1406.
12 Wang PD. Assessment of the need for universal BCG vaccination
of children in Taipei. Public Health 2009;123:74-77.
13 Bowerman RJ. Tuberculin skin testing in BCG-vaccinated
populations of adults and children at high risk for tuberculosis in
Taiwan. Int J Tuberc Lung Dis 2004;8:1228-1233.
14 Chadha VK. Tuberculin test. Indian J Pediatr 2001;68:53-58.
15 Araujo Z, de Waard JH, de Larrea CF, Borges R, Convit J.
The effect of Bacille Calmette-Gurin vaccine on tuberculin
reactivity in indigenous children from communities with high
prevalence of tuberculosis. Vaccine 2008;26:5575-5581.
16 Pieiro R, Mellado MJ, Cilleruelo MJ, Garca-Ascaso M,
Medina-Claros A, Garca-Hortelano M. Tuberculin skin test in
bacille Calmette-Gurin vaccinated children: How should we
interpret the results? Eur J Pediatr 2012;171:1625-1632.
17 Wang L, Turner MO, Elwood RK, Schulzer M, FitzGerald
JM. A meta-analysis of the effect of Bacille Calmette Gurin
vaccination on tuberculin skin test measurements. Thorax
2002;57:804-809.
18 Joint Tuberculosis Committee of the British Thoracic Society.
Chemotherapy and management of tuberculosis in the United
Kingdom: recommendation 1998. Thorax 1998;53:536-548.
19 Guidance for national tuberculosis programmes on the
management of tuberculosis in children. Chapter 1: introduction
and diagnosis of tuberculosis in children. Int J Tuberc Lung Dis
2006;10:1091-1097.
20 Centers for Disease Control. Taiwan Guidelines for TB
Diagnosis and Treatment. Centers for Disease Control, Taiwan,
2011.
21 Starke JR, Taylor-Watts KT. Tuberculosis in the pediatric
population of Houston, Texas. Pediatrics 1989;84:28-35.
22 Pieiro R, Cilleruelo MJ, Mellado MJ. Indications and
interpretation of tuberculin skin test. Form Act Pediatr Aten Prim
2010;3:114-116.
23 Pieiro R, Cilleruelo MJ, Garca-Hortelano M, Garca-Ascaso
M, Medina-Claros A, Mellado MJ. Effect of nutritional status
on tuberculin skin testing. Indian J Pediatr 2012; DOI:10.1007/
s12098-012-0773-1.
24 Pieiro-Prez R, Garca-Hortelano M, Mellado MJ, GarcaAscaso M, Medina-Claros A, Fernndez N, et al. Is there
interference in the interpretation of the tuberculin skin test in
children with intestinal parasitic infestation? Pathog Glob Health
2012;3:172-176.
25 Larsson LO, Bentzon MW, Lind A, Magnusson M, Sandegrd
G, Skoogh BE, et al. Sensitivity to sensitins and tuberculin in
Swedish children. Part 5: A study of school children in an inland
rural area. Tuber Lung Dis 1993;74:371-376.
26 Sepulveda RL, Burr C, Ferrer X, Sorensen RU. Booster effect
of tuberculin testing in healthy 6-year-old school children
vaccinated with Bacillus Calmette-Gurin at birth in Santiago,
Chile. Pediatr Infect Dis J 1988;7:578-581.
27 Arend SM, Thijsen SF, Leyten EM, Bouwman JJ, Franken WP,
Koster BF, et al. Comparison of two interferon-gamma assays
and tuberculin skin test for tracing tuberculosis contacts. Am J
Respir Crit Care Med 2007;175:618-627.
28 Detjen AK, Keil T, Roll S, Hauer B, Mauch H, Wahn U, et
al. Interferon-gamma release assays improve the diagnosis
of tuberculosis and nontuberculous mycobacterial disease in
children in a country with a low incidence of tuberculosis. Clin
Infect Dis 2007;45:322-328.
29 Cordova J, Shiloh R, Gilman RH, Sheen P, Martin L, Arenas
F, et al. Evaluation of molecular tools for detection and drug

World Journal of Pediatrics

Review article

tuberculosis infection without apparent disease? An Pediatr

(Barc) 2007;67:585-593.
46 Andronikou S, Vanhoenacker FM, De Backer AI. Advances
in imaging chest tuberculosis: blurring of differences between
children and adults. Clin Chest Med 2009;30:717-744, viii.
47 De Backer AI, Mortel KJ, Vanhoenacker FM, Parizel PM.
Imaging of extraspinal musculoskeletal tuberculosis. Eur J
Radiol 2006;57:119-130.
48 Singh M, Moosa NV, Kumar L, Sharma M. Role of gastric
lavage and broncho-alveolar lavage in the bacteriological
diagnosis of childhood pulmonary tuberculosis. Indian Pediatr
2000;37:947-951.
49 Zar HJ, Hanslo D, Apolles P, Swingler G, Hussey G. Induced
sputum versus gastric lavage for microbiological confirmation
of pulmonary tuberculosis in infants and young children: a
prospective study. Lancet 2005;365:130-134.
50 Ba F, Rieder HL. A comparison of fluorescence microscopy with
the Ziehl-Neelsen technique in the examination of sputum for
acid-fast bacilli. Int J Tuberc Lung 1999;3:1101-1105.
51 Steingart KR, Henry M, Ng V, Hopewell PC, Ramsay A,
Cunningham J, et al. Fluorescence versus conventional sputum
smear microscopy for tuberculosis: a systematic review. Lancet
Infect Dis 2006;6:570-581.
52 Marais BJ, Brittle W, Painczyk K, Hesseling AC, Beyers N,
Wasserman E, et al. Use of light-emitting diode fluorescence
microscopy to detect acid-fast bacilli in sputum. Clin Infect Dis
2008;47:203-207.
53 Siddiqi S, Ahmed A, Asif S, Behera D, Javaid M, Jani J, et al.
Direct drug susceptibility testing of Mycobacterium tuberculosis
for rapid detection of multidrug resistance using the Bactec
MGIT 960 system: a multicenter study. J Clin Microbiol
2012;50:435-440.
54 Kcocagz T, Altin S, Trkylmaz , Ta , Karaduman P, Bolaban
D, et al. Efficiency of TK culture system in the diagnosis of
tuberculosis. Diag Microbiol Infect Dis 2012;72:350-357.
55 Kolk A, Hoelscher M, Maboko L, Jung J, Kuijper S, Cauchi
M, et al. Electronic-nose technology using sputum samples
in diagnosis of patients with tuberculosis. J Clin Microbiol
2010;48:4235-4238.
56 Kim JH, Kim YJ, Ki CS, Kim JY, Lee NY. Evaluation of Cobas
TeqMan MTB PCR for detection of mycobacterium tuberculosis.
J Clin Microbiol 2011;49:173.
57 Boehme CC, Nabeta P, Hillemann D, Nicol MP, Shenai S, Krapp
F, et al. Rapid molecular detection of tuberculosis and rifampin
resistance. N Engl J Med 2010;363:1005-1015.
58 Papaventsis D, Ioannidis P, Karabela S, Nikolaou S, Syridou
G, Marinou I, et al. Impact of Gen-Probe Amplified MTD test
on tuberculosis diagnosis in children. Int J Tuberc Lung Dis
2012;16:384-389.
59 World Health Organization. Molecular line probe assays for rapid
screening of patients at risk of multidrug-resistant tuberculosis
(MDR-TB). Geneva: World Health Organization, 2008.
60 Graham SM. Treatment of paediatric TB: revised WHO
guidelines. Paediatr Respir Rev 2011;12:22-26.
61 Schoeman JF, Van Zyl LE, Laubscher JA, Donald PR. Effect of
corticosteroids on intracranial pressure, computed tomographic
findings, and clinical outcome in young children with tuberculous
meningitis. Pediatrics 1997;99:226-231.
62 World Health Organization. Rapid advice: treatment of
tuberculosis in children. World Health Organization, Geneva,
Switzerland, 2010.
63 Jassal MS, Aldrovandi GM. 2050: Ending the odyssey of the
great white plague. Pharmacol Res 2011;64:176-179.
64 Koul A, Arnoult E, Lounis N, Guillemont J, Andries K. The
16

challenge of new drug discovery for tuberculosis. Nature

2011;469:483-490.
65 Nair N. Childhood tuberculosis: public health and contact
tracing. Pediatr Respir Rev 2001;2:97-102.
66 Kochi A, Nunn P, Dye C, Taylor E. Global burden of disease.
Lancet 1997;350:142.
67 Gandhi NR, Moll A, Sturm AW, Pawinski R, Govender T, Lalloo
U, et al. Extensively drug-resistant tuberculosis as a cause of
death in patients co-infected with tuberculosis and HIV in a rural
area of South Africa. Lancet 2006;368:1575-1580.
68 Guidance for national tuberculosis and HIV programmes on
the management of tuberculosis in HIV infected children:
recommendations for a public health approach, 2010. Paris:
International Union Against Tuberculosis and Lung Disease,
2010.
69 Migliori GB, Sotgiu G, Gandhi NR, Falzon D, Deriemer K,
Centis R, et al. Drug resistance beyond XDR-TB: results from
a large individual patient data meta-analysis. Eur Respir J 2012;
DOI: 10.1183/09031936.00136312.
70 Seddon JA, Godfrey-Faussett P, Hesseling AC, Gie RP, Beyers
N, Schaaf HS. Management of children exposed to multidrugresistant Mycobacterium tuberculosis. Lancet Infect Dis
2012;12:469-479.
71 Orenstein EW, Basu S, Shah NS, Andrews JR, Friedland
GH, Moll AP, et al. Treatment outcomes among patients with
multidrug-resistant tuberculosis: systematic review and metaanalysis. Lancet Infect Dis 2009;9:153-161.
72 Ettehad D, Schaaf HS, Seddon JA, Cooke GS, Ford N. Treatment
outcomes for children with multidrug-resistant tuberculosis:
a systematic review and meta-analysis. Lancet Infect Dis
2012;12:449-456.
73 Ahuja SD, Ashkin D, Avendano M, Banerjee R, Bauer M,
Bayona JN, et al. Multidrug resistant pulmonary tuberculosis
treatment regimens and patient outcomes: an individual
patient data meta-analysis of 9,153 patients. PLoS Med
2012;9:e1001300.
74 Wells CD, Cegielski JP, Nelson LJ, Laserson KF, Holtz
TH, Finlay A, et al. HIV infection and multidrug-resistant
tuberculosis: the perfect storm. J Infect Dis 2007;196:S86-S107.
75 WHO. Guidelines for the programmatic management of drugresistant tuberculosis. Geneva: World Health Organization, 2006.
http://whqlibdoc.who.int/publications/2006/9241546956_eng.
pdf (accessed June 19, 2008).
76 World Health Organization. Report of the meeting on TB
medicines for children- July 2008. World Health Organization,
Geneva, 2008. http://who.int/selection_medicines/committes/
subcommittee/2/en/index.html (accessed June 19, 2012).
77 American Thoracic Society and Centers for Disease Control and
Prevention. Targeted tuberculin testing and treatment of latent
tuberculosis infection. MMWR Recomm Rep 2000;49:1-51.
78 Lobue P, Menzies D. Treatment of latent tuberculosis infection:
an update. Respirology 2010;15:603-622.
79 Comstock G. How much isoniazid is needed for prevention of
tuberculosis among immunocompetent adults? Int J Tuberc Lung
Dis 1999;3:847-850.
80 Spyridis NP, Spyridis PG, Gelesme A, Sypsa V, Valianatou
M, Metsou F, et al. The effectiveness of a 9-month regimen of
isoniazid alone versus 3- and 4-month regimens of isoniazid
plus rifampin for treatment of latent tuberculosis infection in
children: results of an 11-year randomized study. Clin Infect Dis
2007;45:715-722.
Received October 1, 2012
Accepted November 27, 2012

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